Selection of HER-2/neu-positive tumor cells in early stage cervical cancer: implications for Herceptin-mediated therapy
Selection of HER-2/neu-positive tumor cells in early stage cervical cancer: implications for Herceptin-mediated therapy
复制标题
DOI：
10.1016/s0090-8258(03)00460-8
复制
发表时间：
2003-10-01
影响因子：
4.7
通讯作者：
Santin, AD
中科院分区：
文献类型：
--
作者：
Bellone, S;Palmieri, M;Santin, AD
目标.本研究的目的是比较从早期宫颈癌、由其建立的原代细胞系、建立的宫颈癌细胞系和疾病的转移或复发部位获得的活检组织上的HER-2/neu表达;并评估原代宫颈癌细胞系对用针对HER-2/neu的人源化MAb（赫赛汀）治疗的敏感性。将18个宫颈癌细胞系的表面HER-2/neu表达与通过免疫组织化学对从原始肿瘤（10名患者）和复发部位（2名患者）获得的活检组织的HER-2/neu检测进行比较。检测原代细胞系对赫赛汀介导的抗体依赖性细胞毒性（ADCC）的敏感性和对赫赛汀介导的增殖抑制的敏感性。流式细胞术检测10株原代宫颈癌细胞中有9株（90%）和8株（100%）建立的宫颈癌细胞系表达HER-2/neu。令人惊讶的是，所有HER-2/neu阳性原代细胞系均来源于评分为阴性的肿瘤活检（即，0至1+）的HER-2/neu表达。HER-2/neu的重染色（即，3+）。重要的是，所有HER-2/neu阳性原代细胞系对赫赛汀介导的ADCC高度敏感，其增殖也被赫赛汀显著抑制。结果表明，低剂量IL-2可显著增强效应细胞对赫赛汀介导的ADCC的反应。早期宫颈癌可能会形成HER-2/neu阳性细胞群，其选择性生长优势超过HER-2/neu阴性细胞。靶向HER-2/neu的治疗在宫颈癌患者中可能比在初次治疗时切除的肿瘤中HER-2/neu的低表达所指示的更有效。(C)2003年爱思唯尔公司All rights reserved.
Objectives. The purpose of this study was to compare HER-2/neu expression on biopsies obtained from early stage cervical cancer, primary cell lines established therefrom, established cervical cancer cell lines, and metastatic or recurrent sites of disease; and to evaluate the sensitivity of primary cervical cancer cell lines to treatment with a humanized MAb against HER-2/neu (Herceptin).Methods. Surface HER-2/neu expression on 18 cervical cancer cell lines was compared to HER-2/neu detection by immunohistochemistry on biopsies obtained from the original tumors (10 patients) and sites of recurrence (2 patients). Primary cell lines were tested for sensitivity to Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC) and sensitivity to Herceptin-mediated inhibition of proliferation.Results. Nine out of 10 primary (90%) and 8 out of 8 (100%) established cervical cancer cell lines expressed HER-2/neu by flow cytometry. Surprisingly, all HER-2/neu-positive primary cell lines were derived from tumor biopsies that scored negative (i.e., 0 to 1+) for HER-2/neu expression by immunohistochemistry. Heavy staining for HER-2/neu (i.e., 3+) was found in the recurrent/metastatic lesions of the two relapsed patients. Importantly, all HER-2/neu-positive primary cell lines were highly sensitive to Herceptin-mediated ADCC, and their proliferation was also significantly inhibited by Herceptin. A significant enhancement of Herceptin-mediated ADCC was demonstrated when effector cells were exposed to low doses of IL-2 in vitro.Conclusions. Early stage cervical cancer may develop a population of HER-2/neu-positive cells with a selective growth advantage over HER-2/neu-negative cells. Therapy which targets HER-2/neu may be more effective in patients with cervical cancer than indicated by the commonly low expression of HER-2/neu in tumors removed at the time of primary treatment. (C) 2003 Elsevier Inc. All rights reserved.